Integration of functional precision oncology to immune contexture predicts immunotherapies strategies for mucosal melanomas.

Mucosal melanomas (MM) arise from mucosal melanocytes at various anatomical sites. These tumors are rare, highly aggressive, and often associated with poor outcomes. Current treatments, including immune checkpoint inhibitors, show limited efficacy in advanced disease. Compared to cutaneous melanomas, there is a lack of data on the immunogenicity and IFN-γ sensitivity of MM. In this study, we examine these features in sino-nasal melanoma (SN-MM) cell lines and clinical samples using microscopy and functional genomics. Microscopic analysis reveals that most SN-MM tumors are immune "desert" with few tumor-infiltrating lymphocytes (TILs), a characteristic linked to poor prognosis. Additionally, SN-MM tumors are CD274/PD-L1 negative. SN-MM cell lines express transcripts for melanocytic and cancer testis antigens. They also show normal surface expression of IFN-γ receptors (IFNGR) and maintain the integrity of the IFNGR/JAK/STAT signaling pathway. Transcriptomic and proteomic analyses demonstrate that SN-MM cell lines, as a group, respond to IFN-γ by upregulating genes involved in immune recognition and antigen presentation. In 60% of SN-MM lines, IFN-γ also induces cytotoxic and anti-proliferative effects, the release of CXCL10 and upregulation of CD274/PD-L1. The remaining SN-MM cell lines, characterized by poor differentiation, show refractoriness to these effects, likely due to post-transcriptional regulation. These findings suggest that combining functional precision oncology with immune context analysis could refine our understanding of immune escape mechanisms in MM and improve patient stratification for immune therapies.